A majority of human epithelial ovarian tumors express elevated levels of the antigen CA125. This antigen is a repeating peptide epitope located on the mucin MUC16. Elevations in the serum concentration of CA125 are routinely determined in order to monitor the progression of epithelial ovarian cancer in patients undergoing treatment for this disease.
MUC16 is a mucin with an average molecular weight of 5 million Da. Contributing to this high molecular weight of MUC16 are the over 22,000 amino acids that make up the protein backbone and the extensive N-linked and O-linked oligosaccharide chains. This mucin is cell surface bound mucin and expressed on the ovarian, endometrial, and ocular surface epithelial cells. Cell surface bound MUC16 (csMUC16) carries an extensive N-terminal epitope followed by approximately 60 tandem repeats that are each composed of 156 amino acids. A transmembrane segment attaches the mucin to the cell surface and is followed by a short cytoplasmic tail. Proteolytic cleavage at a site upstream of the transmembrane segment results in shedding of MUC16 from the cell surface. The shed MUC16 (sMUC16) is released in the peritoneal fluid (PF) of ovarian cancer patients or may leak into the systemic circulation where it can be detected by using the serum CA125 assay.
It was recently shown that natural killer (NK) cells isolated from the peripheral blood (PB) and the PF of ovarian cancer patients are recognized by anti-MUC16 antibodies. RT-PCR and other in vitro experiments demonstrate that the NK cells do not synthesize this mucin but instead acquire the sMUC16 that is shed from the ovarian cancer cells. Even though the amount of sMUC16 in the PB of ovarian cancer patients is 10-100-fold lower than the PF, robust amounts of sMUC16 were detected on the NK cells in peripheral circulation.
At present, CA125 is a widely utilized biomarker for ovarian cancer. CA125 levels in serum do rise in ovarian cancer, but also in pregnancy and endometriosis. Even though CA125 is not specific for ovarian cancer, it has proven to be useful as a prognostic after diagnosis and therapy for monitoring for recurrence of disease. After treatment, the baseline level of CA125 achieved is somewhat prognostic for time-frame to tumor recurrence. CA125 levels up to 35 U/ml are considered normal, while levels over two times this amount are considered abnormal. Several publications link the production of MUC16 to a suppression of immune response in the host as well as to tumor metastasis in the peritoneal cavity.
Unfortunately, CA125 assays give high levels of false positives, making this a poor screening tool for the general population. In addition, CA125 levels may also rise in alcoholic liver disease, pleurisy, and bronchitis. Therefore, the reliability of this marker in terms of sensitivity and specificity is not entirely satisfactory. An improved biomarker with better diagnostic capability is desperately needed in the art.